Granulocyte colony stimulating factor (GCSF or CSF3) exerts its function via the activation of a membrane receptor, the colony stimulating factor 3 receptor (CSF3R), that belongs to the super-family of hematopoietin receptors, also being referred to as class I cytokine receptors. CSF3R is also known as the granulocyte colony stimulating factor receptor (GCSFR) or CD7 114.
A number of receptors for lymphokines, hematopoietic growth factors, and growth hormone-related molecules have been found to share a common binding domain. These receptors are referred to as hematopoietin receptors and the corresponding ligands as hematopoietins. Further, hematopoietins have been subdivided into two major structural groups: Large/long and small/short hematopoietins. One subset of individual receptor chains that are part of receptor complexes for large hematopoietins contain common structural elements in their extracellular parts: an immunoglobin-like domain, a hematopoietin-receptor domain, and 3 fibronectin type-III domains (2 in the leptin receptor). This subgroup was designated the “gp130 family of receptors” (Mosley, et al. J. Biol. Chem. 1996, 271, 32635-43) and include Leptin receptor (LPTR), Granulocyte colony stimulating factor receptor (GCSFR), Interleukin-6/-11/LIF/OSM/CNTF common beta chain (GP130), Leukemia inhibiting factor receptor (LIFR), Oncostatin-M receptor beta chain (OSMR), interleukin-12 receptor beta-1 chain (IL12RB1), Interleukin-12 receptor beta-2 chain (IL12RB2). These receptor chains homodimerize (GCSFR, GP130, LPTR) or heterodimerize (GP130 with LIFR or OSMR, IL12RB1 with IL12RB2) upon binding the cognate cytokine.
The human CSF3R protein is a 826 amino acid polypeptide comprising a signal peptide (amino acid residues 1-24), an extracellular domain, located within the N-terminal region of the protein (amino acid residues 25-627), an intracellular domain (amino acid residues 651-836) and a transmembrane region (amino acid residues 628-650). The extracellular portion contains an N-terminal immunoglobulin (Ig)-like domain (amino acid residues 25 to 117), a cytokine receptor homology (CRH) domain (amino acid residues 122 to 330), and 3 fibronectin type III (FNIII) domains. Within the CRH region are 2 FNIII domains, 4 conserved cysteine residues, and a conserved WSXWS motif (amino acid residues 318 to 322) that stabilizes the CRH domain. The Ig-like and CRH domains appear to be critical for high-affinity binding. A box 1 motif is present in the intracellular domain (amino acid residues 658 to 666) required for JAK interaction and/or activation.
GCSF stimulates proliferation, survival, and maturation of cells committed to the neutrophilic granulocyte lineage through binding to the specific GCSF receptor (see Hartung T., et al., Curr. Opin. Hematol. 1998; 5: 221-5). The CSF3R receptor possesses no intrinsic kinase activity in the cytoplasmic domain and uses receptor-associated intracellular protein kinases such as the Janus tyrosine kinases (JAKs) to initiate signal transduction. Stimulation of cells with G-CSF has been shown to activate multiple signal transduction pathways, including Signal Transducer and Activators of Transcription (STATs), Ras/Raf/Erk, phosphatidylinositol 3-kinase (PI3-K)/Akt, but also Stat proteases such as the Stat5 protease. Deregulated Stat5 activation may lead to aberrant cellular responses to CSF3 and contribute to leukemogenesis.
GCSF is typically used for the treatment of different kinds of neutropenia in humans. It is one of the few growth factors approved for clinical use. In particular, it is used to reduce chemotherapy (CT)-induced cytopenia (Viens et al., J. of Clin. Oncology, Vol. 20, No. 1, 2002: 24-36). GCSF has also been implicated for therapeutic use in infectious diseases as potential adjunctive agent (Hubel et al., J. of Infectious Diseases, Vol. 185: 1490-501, 2002).
In a mouse model of myocardial infarction, CSF3 treatment did not affect initial infarct size at day 3 but improved cardiac function as early as 1 week postinfarction, and the beneficial effects were reduced by delayed start of treatment (Harada et al. Nature Med. Vol. 11: 305-311, 2005). CSF3 induced antiapoptotic proteins and inhibited apoptotic death of cardiomyocytes, and CSF3 also reduced apoptosis of endothelial cells and increased vascularization in the infarcted hearts. Harada et al. suggested that CSF3 promotes survival of cardiac myocytes and prevents left ventricular remodeling after myocardial infarction.
Application of a single dose of G-CSF in patients with community-acquired pneumonia (CAP) caused a prolonged survival and increased activation of neutrophils combined with a sustained release of anti-inflammatory cytokines (Droemann et al. Respiration. 2005 Dec. 12. Epub ahead of print).
CSF3 is also beneficial for the prevention and/or treatment of immune-mediated diseases, e.g. graft-vs-host disease, multiple sclerosis, systemic lupus erythematosus, inflammatory bowel disease, and diabetes (Rutella et al. J. Immunol. 2005 Dec. 1; 175(11):7085-91).